Acenaphthyloxazole derivatives

ABSTRACT

In addition, intermediates and a process for preparing the acenaphthyloxazoles are provided, which process comprises reacting an acenaphthenequinone with ethylene glycol in the presence of p-toluenesulfonic acid to form an acenaphthenequinone monoethylene ketal, reducing the ketal to the corresponding 1hydroxy-2-acenaphthenone monoethylene ketal, hydrolyzing the ketal and reacting the resulting 1-hydroxy-2-acenaphthenone with succinic acid or acid anhydride to form the corresponding succinate and reacting the succinate with ammonium acetate and acetic acid to form the compounds of the invention.

United States Patent Levine 51 July 11, 1972 [54] ACENAPHTHYLOXAZOLEPrimary ExaminerAlex Maze] DERIVATIVES Assistant Examiner-R. V. Rush[72] Inventor: Seymour D. Levine, North Brunswick, NJ. gzgggggafiggiiakgMerle J. smlth Donald J. [73] Assignee: E. R. Squibb & Sons, Inc.,Princeton. NJ. [22] Filed: Feb. 2, 1970 [57] ABSTRACT Appl. No.: 8,016

References Cited UNITED STATES PATENTS 10/1950 Johnson et a] ..260/465In addition, intermediates and a process for preparing theacenaphthyloxazoles are provided, which process comprises reacting anacenaphthenequinone with ethylene glycol in the presence ofp-toluenesulfonic acid to form an acenaphthenequinone monoethyleneketal, reducing the ketal to the correspondingl-hydroxy-2-acenaphthenone monoethylene ketal, hydrolyzing the ketal andreacting the resulting l-hydroxy-2-acenaphthenone with succinic acid oracid anhydride to form the corresponding succinate and reacting thesuccinate with ammonium acetate and acetic acid to form the compounds ofthe invention.

7 Claims, No Drawings ACENAPl-ITHYLOXAZOLE DERIVATIVES (3) The presentinvention relates to acenaphthyloxazole derivatives which are useful asanti-inflammatory agents and are effective in warm-blooded animals, forexample, in a manner similar to indomethacin. They may be used todecrease joint 5 swelling, tenderness, pain and stiffness in mammalianspecies, e.g., in conditions such as rheumatoid arthritis. A compound offormula 1 (below) may be compounded according to accepted pharmaceuticalpractice in oral dosage forms such as tablets, capsules, elixirs orpowders for administration of about 100 mg. to 2 gm. per day, preferably100 mg. to 1 gm. per day in two to four divided doses.

The acenaphthyloxazoles of the invention have the general (4) formula:

R 13 15 R (!3( 3C 0 0 H a x- X wherein the Xs can be the same ordifferent and are hydrogen, halogen, nitro, lower alkoxy having from oneto about four carbon atoms, or halolower alkoxy having from one to aboutfour carbon atoms, and R, R R and R can be the same or different and arehydrogen or lower alkyl having from one to about four carbon atoms.

Examples of lower alkyl radicals included in the compounds of theinvention are straight or branched chain radicals and include methyl,ethyl, propyl, isopropyl, n-butyl, and the like.

Examples of suitable alkoxy radicals are those corresponding to theforegoing alkyl radicals.

The halogen may be F, Cl, Br or I.

Alkoxy radicals substituted by F, Br, Cl or I are encompassed by theterms haloalkoxy. Trifluorornethoxy is a preferred haloalkoxy radical.

The compounds of particular interest are acenaphthyloxazolesunsubstituted in the aromatic ring' or the para-substituted symmetricalderivatives thereof. Furthermore, the pair of R radicals on the alphacarbon atom of the acid substituent should correspond to the pair of Rradicals on the beta carbon atom.

Exemplary of acenaphthyloxazoles falling within the present inventioninclude, but are not limited to, the following: (7)

1) CHzCHzC 0211 omcnzcoln C 3 omcmcozn c I FaC O@OCF: I I (:1 c1

Further in accordance with the present invention, a process I5 isprovided for preparing the acenaphthyloxazoles of the invention. Theprocess of the invention is outlined below:

I OCHaCl CHaCH-CHC 01H &

m 1 O l m l C w 0 3 C O m H .C C

I No:

CHgCHzC 01H The process of the invention comprises reacting anacenaphthenequinone (II) with ethylene glycol in the presence of an acidcatalyst, preferably, p-toluenesulfonic acid, and a solvent, to form anacenaphthenequinone monoethylene ketal (formula III), reducing theacenaphthenequinone monoethylene ketal with a metal hydride to form a1-hydroxy-2-acenaphthenone monoethylene ketal (formula IV).

The l-hydroxy-2-acenaphthenone monoethylene ketal (IV) can be hydrolyzedby treatment with an acid catalyst, such as p-toluene-sulfonic acid, inan aqueous acetone medium to form a l-hydroxy-2-acenaphthenone(V) whichis reacted with a succinic acid or acid anhydride in the presence of abase to form a l-hydroxy-2-acenaphthenone succinate (VII).

Alternatively, the l-hydroxy-2-acenaphthenone succinate (VII) can beformed by reacting the l-hydroxy-Z- acenaphthenone ethylene ketal (IV)with a succinic acid or acid anhydride in the presence of a base to forma l-hydroxy- Z-acenaphthenone ethylene ketal succinate (VI) and thenhydrolyzing the ethylene ketal of the succinate (VI) by treating it withan acid catalyst, for example, p-toluenesulfonic acid, in an aqueousacetone medium to form the l-hydroxy-Z- acenaphthenone succinate (VII).

The l-hydroxy-Z-acenaphthenone succinate (VII), formed by either of theabove procedures, can be converted to the acenapht[l,2-d]oxazole-8-propionic acid (formula I) of the invention by reactingthe succinate with ammonium acetate in acetic acid.

The intermediates III, IV, V, VI and VII prepared in forming theacenaphthyloxamles are novel compounds. These intermediates can bedefined by the general formula:

l l X X wherein Y and Z are different and Y can be =0, OI-I, or

0 l O CH2CHrCOzH and Z can be 0-1 or =0;

X is as defined hereinbefore.

The starting materials employed in preparing the acenaphthyloxazoles ofthe invention are acenaphthenequinones of the formula II which may beprepared by the oxidation of an X-substituted acenaphthene. Oxidizingagents, such as chromic acid, calcium permanganate, hydrogen peroxide inacetic acid or sodium dichromate in acetic acid can be employed. Whenthe starting acenaphthenequinone is unsymmetrically substituted, then,in such case, the monoketal product obtained will be a mixture ofisomers. Thus, for example, where the acenaphthenequinone includes anX-substituent at one para-position, then two monoketal isomers arepossible, namely,

Themixtures of isomers can be separated by thin layer or vapor phasechromatographic techniques.

In preparing the acenaphthenequinone monoethylene ketal (formula III),the acenaphthenequinone is reacted with ethylene glycol in at leastequimolar amounts and can be reacted in a mole ratio ofacenaphthenequinone:ethylene glycol of up to 1:l00 or more. The solventin the reaction can be an aromatic solvent having a boiling point of 80C. or higher, such as benzene, toluene or xylene. The reaction to formthe monoethylene ketal III is normally carried out at the boilingtemperature of the solvent.

Reduction of the acenaphthenequinone monoethylene ketal (III) to thel-hydroxy-2-acenaphthenone ethylene ketal (IV) is carried out employinga metal hydride reducing agent, such as an alkali metal borohydride, forexample, sodium borohydride, potassium borohydride, or lithiumborohydride, or lithium aluminum hydride. The solvent employed in thereduction can be an alcohol containing up to about four carbon atoms,such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropylalcohol, n-butyl alcohol, sec-butyl alcohol, or tert-butyl alcohol oradmixtures of the alcohol with water. In addition, dioxane ortetrahydrofuran can be used. The reduction is preferably conducted atroom temperature, although temperatures as high as the boiling point ofthe solvent can be employed.

Hydrolysis of the l-hydroxy-Z-acenaphthenone ethylene ketal (IV) to thel-hydroxy-2-acenaphthenone (V) is carried out in an aqueous acetonemedia containing an acid catalyst, such as p-toluene sulfonic acid.

The l-hydroxy-2-acenaphthenone (V) is converted to the correspondingsuccinate by reaction with a succinic acid or acid anhydride in thepresence of an organic base or an inorganic base, such as pyridine,sodium acetate or potassium acetate. The succinic acid or acid anhydridecan include alkyl substituents on the alpha and beta carbon atoms.However, the acid or acid anhydride should be symmetrical with respectto such alkyl substituents so that the substituents on the alphacarboncorrespond to the substituents on the beta-carbon atom. The succinicacid or acid anhydride is reacted with lhydroxy-Z-acenaphthenone (V) inequimolar quantities. However, large excesses of the succinic acid oranhydride may be employed, for example, excesses of 100 percent or more.The reaction to form the succinate (VII) can be carried out at roomtemperature, although temperatures as high as 100 C. or more can beemployed.

The l-hydroxy-Z-acenaphthenone ethylene ketal can be first reacted withsuccinic acid or acid anhydride to form the l-hydroxy-Z-acenaphthenoneethylene ketal succinate (VI) and this ketal can be hydrolyzed to fonnthe l-hydroxy-2- acenaphthenone succinate (VII). The reactionconditions, reactants and mole ratios employed are essentially the sameas those described hereinbefore in. the .ketal hydrolysis andesterifrcation of the l-hydroxy-2-acenaphthenone ethylene ketal (IV) tothe l-hydroxy-'2-acenaphthenone succinate (VII).

The succinate (VII) is then converted to the correspondingacenaphthyloxazole by reaction with ammonium acetate in the presence ofacetic acid at temperatures ranging from EXAMPLE I AcenaphthenequinoneMonoethylene Ketal A mixture of l g. of acenaphthenequinone and 50 mg.of ptoluenesulfonic acid in 5 ml. of ethylene glycol and 50 ml. ofbenzene is stirred and refluxed overnight. The mixture is cooled and thebenzene layer separated. The glycol layer is diluted with water andextracted with benzene. The benzene Anal. Calc'd for C H O -,(226.22):

Found:

The product of intermediate polarity is crystallized fromchloroform-isopropyl ether to give the acenaphtho[l,2-b]bis[l,4]2l3.5214.

Anal. Calc'd for C H OA 270.27):

Found:

The most polar product is crystallized from chloroformisopropyl ether togive acenaphthenequinone bis-ethylene ketalmp l47.5148.

Anal. Calc'd for C|6HNO4(27O.27): C, 7l.l0, H, 5.22 Found: C, 7l.23, H,5.48

EXAMPLE 2 l-Hydroxy-Z-Acenaphthenone Ethylene Ketal A solution of 444mg. of acenaphthenequinone monoethylene ketal in 50 ml. of methanol istreated with 130 mg. of sodium borohydride and stirred at roomtemperature for 2 hours. The mixture is treated with acetic acid,concentrated and diluted with water. The precipitate is collected byfiltration to give the title compound, m.p. ll2l 13.5".Recrystallization from isopropyl ether gives the analytical sample: m.p.ll3l l4.5; 2.94;.1. Anal. Calcd for C,4H,2O3(228.24):

Found: C, 73.45; H, 5.17.

EXAMPLE 3 l-Hydroxy-Z-Acenaphthenone A mixture of 143 mg. ofl-hydroxy-2-acenaphthenone ethylene ketal and 15 mg. ofp-toluenesulfonic acid in 1 ml. of water and 20 ml. of acetone isrefluxed overnight. The mixture is concentrated, diluted with water andextracted with chloroform. The chloroform extracts are washed with 8percent salt solution, dried (Na SO and evaporated to give the titlecompound.

EXAMPLE 4 l-Hydroxy-2-Acenaphthenone Ethylene Ketal Succinate A mixtureof 2 g. of l-hydroxy-2-acenaphthenone ethylene ketal and 2 g. ofsuccinic anhydride in 10 ml. of pyridine is stirred at room temperaturefor 3 days. The mixture is diluted with water and extracted withchloroform. The chloroform extracts are washed with 8 percent saltsolution, dried (Na SO and evaporated to dryness. The residue iscrystallized from acetone-hexane-ether to give 2.53 g. of the titlecompound, m.p. ll-1 12. Recrystallization from acetone-hexane-ethergives the analytical sample: m.p. l 1()-l l l.5; A 5.75 and 5.86;!"

Anal. Calcd for C,,H, O 328.33):

Found:

EXAMPLE l-Hydroxy-Z-Acenaphthenone Succinate A. Following the procedureof Example 4 but substituting lhydroxy-Z-acenaphthenone forl-hydroxy-2-acenaphthenone ethylene ketal, there is obtained the titlecompound: FTMS 7.20 (S,-(CH,) and 3.65 s, 1-H). CD01 B. Following theprocedure of Example 3 but substituting lhydroxy-Z-acenaphthenoneethylene ketal succinate for lhydroxy-Z-acenaphthenone ethylene ketal,there is obtained the title compound.

EXAMPLE 6 Acenapht[ l,2-d]oxazole-8-Propionic Acid A mixture of l g. ofI-hydroxy-Z-acenaphthenone-succinate and 2 g. of ammonium acetate in 20ml. of acetic acid is warmed at 50 for 1 hour. The mixture is cooled,diluted with water and extracted with chloroform. The chloroformextracts are washed with 8 percent salt solution, dried (Na SO andevaporated to give the title compound.

What is claimed is:

1. An acenaphthyloxazole of the general formula wherein the Xs can bethe same or different and are selected from the group consisting ofhydrogen, halogen, nitro, lower alkoxy having from one to four carbonatoms or halo-lower alkoxy having from one to four carbon atoms, and R,R R and R" can be the same or different and are hydrogen or lower alkylhaving from one to four carbon atoms.

2. An acenaphthyloxazole in accordance with claim 1 wherein the pair ofR and R substituents correspond to the pair of R and R substituents.

3. An acenaphthyloxazole in accordance with claim 1 wherein the Xs ateach of the para positions of the acenaphthene ring are other thanhydrogen.

4. An acenaphthyloxazole in accordance with claim I having thestructure:

CHzCHzCOOH C O N 5. A process for preparing acenaphthyloxazolederivatives of claim 1, which comprises reacting an appropriatelysubstituted acenaphthenequinone with ethylene glycol in the presence ofp-toluenesulfonic acid to form an acenaphthenequinone monoethyleneketal, reducing the monoethylene ketal with a metal hydride to form al-hydroxy- 2-acenaphthenone ethylene ketal, convening the l-hydroxy-Z-acenaphthenone ethylene ketal to a l-hydroxy-Z- acenaphthenonesuccinate by subjecting the ketal to (a) hydrolysis in the presence ofp-toluenesulfonic acid, and (b) reaction with a succinic acid or acidanhydride in the presence of a base, (a) and (b) being taken in eitherorder, and reacting l-hydroxy-Z-acenaphthenone succinate with ammoniumacetate in acetic acid to form an acenaphtl l ,2-d]-oxazole-8- propionicacid.

reacting the 1-hydroxy-2-acenaphthenone ethylene ketal with a succinicacid or acid anhydride in the presence of a base selected from the groupconsisting of pyridine, sodium acetate and potassium acetate to form al-hydroxy-2-acenaphthenone ethylene ketal succinate and treating thel-hydroxy-Z- acenaphthenone ethylene ketal succinate in an aqueousacetone medium with p-toluenesulfonic acid to form thelhydroxy-2-acenaphthenone succinate starting material.

, I QA27 27; UNITED STATES PATENT OFFICE Part 1 2 CERTIFICATE OFCORRECTION Patent No. 3 I676 Dated July 11 1972 Inventor(s) Y D- LevineIt is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

In the Abstract, please insert the following as the first paragraphafter'the title "ABSTRACT":

Acenaphthyloxazoles are provided having the general structure:

ll R C(|3COOH I o N X 0 X X X wherein R R R R can be hydrogen or loweralkyl and X is hydrogen, halogen, nitro, alkoxy or haloalkoxy. Thesecompounds possess anti-inflammatory activity.

QAZ?

L" v Part 2 of. 2

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,676.452 v Dated July 11 1972 Inventor) Seymour D. Levine X It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 4 formula IV:

should read: X X

Column 4 formula VII:

should read: X X X X X Column 7, line 15, insert dioxane, m.p. after:

"bis[l,4]".

Signed and sealed this 20th day of February 1973.

(SEAL) Atiest: 1

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents

2. An acenaphthyloxazole in accordance with claim 1 wherein the pair ofR1 and R2 substituents correspond to the pair of R3 and R4 substituents.3. An acenaphthyloxazole in accordance with claim 1 wherein the X''s ateach of the para positions of the acenaphthene ring are other thanhydrogen.
 4. An acenaphthyloxazole in accordance with claim 1 having thestructure:
 5. A process for preparing acenaphthyloxazole derivatives ofclaim 1, which comprises reacting an appropriately substitutedacenaphthenequinone with ethylene glycol in the presence ofp-toluenesulfonic acid to form an acenaphthenequinone monoethyleneketal, reducing the monoethylene ketal with a metal hydride to form a1-hydroxy-2-acenaphthenone ethylene ketal, convertinG the1-hydroxy-2-acenaphthenone ethylene ketal to a1-hydroxy-2-acenaphthenone succinate by subjecting the ketal to (a)hydrolysis in the presence of p-toluenesulfonic acid, and (b) reactionwith a succinic acid or acid anhydride in the presence of a base, (a)and (b) being taken in either order, and reacting1-hydroxy-2-acenaphthenone succinate with ammonium acetate in aceticacid to form an acenapht(1,2-d)-oxazole-8-propionic acid.
 6. A processin accordance with claim 5 which comprises hydrolyzing the1-hydroxy-2-acenaphthenone ethylene ketal by treating it in an aqueousacetone medium in the presence of p-toluenesulfonic acid to form a1-hydroxy-2-acenaphthenone and reacting the 1-hydroxy-2-acenaphthenonewith a succinic acid or acid anhydride in the presence of a baseselected from the group consisting of pyridine, sodium acetate andpotassium acetate to form the 1-hydroxy-2-acenaphthenone succinatestarting material.
 7. A process in accordance with claim 5 whichcomprises reacting the 1-hydroxy-2-acenaphthenone ethylene ketal with asuccinic acid or acid anhydride in the presence of a base selected fromthe group consisting of pyridine, sodium acetate and potassium acetateto form a 1-hydroxy-2-acenaphthenone ethylene ketal succinate andtreating the 1-hydroxy-2-acenaphthenone ethylene ketal succinate in anaqueous acetone medium with p-toluenesulfonic acid to form the1-hydroxy-2-acenaphthenone succinate starting material.